A de novo human MYCBP2 variant enhances memory persistence across species

Exceptional human memory phenotypes provide an entry point to identify rare coding variants that influence memory capacity. Here we studied an individual with highly superior autobiographical memory (HSAM), a rare condition characterized by the exceptional ability to recall personal events across decades with striking detail. The individual showed extraordinary autobiographical recall despite otherwise average cognitive performance. Whole-brain structural imaging revealed exceptionally large volumes in hippocampal subregions previously linked to autobiographical memory. Trio whole-exome sequencing identified a rare de novo MYCBP2 V768F missense variant, absent from more than 700,000 population exomes and affecting an evolutionarily conserved residue in the encoded E3 ubiquitin-protein ligase. To test the functional impact of this human variant, we engineered the homologous substitution in C. elegans and mice. C. elegans carrying the homologous variant showed enhanced long-term associative memory without detectable sensory, motor, or growth changes. Heterozygous Mycbp2 knock-in mice carrying the orthologous substitution showed improved long-term memory retention in spatial and non-spatial memory tasks. Finally, prime editing of the same variant selectively in dorsal hippocampal neurons of adult mice improved spatial long-term memory, indicating that this effect does not require developmental expression. These findings identify a rare de novo human MYCBP2 variant that enhances long-term memory retention across species and provide experimental evidence linking an exceptional human memory phenotype to conserved biology of memory persistence.